My goal is to become an independent investigator in the field of pediatric infectious diseases, with a concentration in metabolic disease associated with pediatric and adolescent HIV infection. Under the guidance of my mentors, Dr. Christopher Duggan and Dr. Tracie Miller, I have developed a comprehensive training plan that will allow me to develop and implement an independent research study, pursue training in clinical research methodologies followed by completion of a Masters in Public Health degree, and learn laboratory techniques for conducting and interpreting assays of mitochondrial dysfunction. Most importantly, I will have the opportunity to work with a national, NIH-funded, multi-center cohort study in which I will have the primary role in the implementation of an independent substudy as well as a leading role in developing future studies in the field of HIV-associated metabolic disease and mitochondrial dysfunction. Environment: Children's Hospital Boston and Harvard School of Public Health are known for their world- renowned faculty, several of whom will serve as mentors and advisors for me and my project, an established Clinical Research Program which provides support for clinical investigators in all aspects of grant and protocol development and implementation, a General Clinical Research Center/Clinical Translational Study Unit, the NIH-funded pan-university,collaborative Harvard Catalyst Program for the establishment of a Clinical and Translational Science Center, and a wide array of educational seminars and training programs designed specifically for faculty who are conducting clinical research. Research: My research endeavor addresses a newly emerging challenge that we face in HIV care - potential adverse effects of antiretroviral therapy (ART). Metabolic complications such insulin resistance and lipid abnormalities are risk factors of premature myocardial infarction, and there is increasing evidence that the mechanism for these metabolic complications, especially insulin resistance, may be mitochondrial dysfunction. Preliminary studies in HIV-infected children indicate that 14% of these children already exhibit insulin resistance by the time they are adolescents. Studies in HIV-infected adults demonstrate that mitochondrial dysfunction occurs in conjunction with ART and that individuals with mitochondrial abnormalities are more likely to have insulin resistance. Our aims are to first characterize body composition abnormalities, nutritional issues, and metabolic complications in HIV-infected children by analyzing a large, existing database of diet, anthropometric measures, laboratory studies (lipid profiles, glucose, insulin) and DEXA scans that have been collected in HIV-infected children over a 19-year period. We will then conduct a national, multi-center study in collaboration with the Pediatric HIV/AIDS Cohort Study (PHACS) to determine whether mitochondrial dysfunction and hyperlactatemia are associated with insulin resistance or specific antiretroviral agents. For this second Aim over 400 HIV-infected children as well as controls will be enrolled, and PBMC and buccal swab assays to detect mitochondrial oxidative phosphorylation abnormalities and evidence of oxidative stress will be conducted. PUBLIC HEALTH RELEVANCE: The development of metabolic abnormalities associated with combination antiretroviral therapy (cART) will have a profound impact on HIV-infected patients worldwide. Although the number of children with perinatally- acquired HIV has diminished in the United States, there remain millions of HIV-infected children worldwide who need cART to treat their HIV disease and survive without progression to AIDS. However, the potential increase in cardiovascular morbidity and diabetic complications associated with cART will affect long-term survival of HIV-infected children, and will increase the burden on healthcare systems everywhere. Children with perinatally-acquired HIV infection will likely require cART for life and represent a unique, disadvantaged population of patients who may develop mitochondrial dysfunction and metabolic complications at a very early age. Given that cART is so critical to the care of HIV-infected children, it is imperative that we understand the mechanisms of these potential toxicities associated with antiretroviral medications. We can then find ways to reduce these effects by devising interventions aimed at preventing or stopping the progression of metabolic disease.